This guide describes the evidence behind the FZD4 review and its important experimental limits. The evidence archive retains all 134 original annotation contexts, their literal donor and partner identifiers, the six extension atoms in five contexts, the canonical sequence and source provenance. Current decisions, reference assessments and core functions belong in the review; they are not duplicated in the archive.
The official reviewed human record, UniProt Q9ULV1, identifies a 537-residue FZD4 precursor with an extracellular cysteine-rich region, seven transmembrane segments and cytoplasmic signaling motifs. It declares no alternative natural products. Signal-peptide processing, isolated extracellular domains, intracellular peptides, stabilizing substitutions and disease variants used in experiments are distinct from natural isoforms. Sequence identity does not establish identical behavior across these engineered constructs.
Two complementary receptor functions organize the synthesis. Human FZD4 functional rescue supports Wnt-dependent canonical signaling, with ligand and cellular context retained. The original PMID:28733458(https://pubmed.ncbi.nlm.nih.gov/28733458/) Methods, Results, Figure 6 and Table 4 include FZD4 responses to Wnt9a/9b even though other Frizzled receptors receive prominent treatment in the abstract. This is functional pathway output, not a purified ligand-affinity measurement. PMID:20802536(https://pubmed.ncbi.nlm.nih.gov/20802536/) tests human HA-FZD4 in hamster CHO cells, Wnt5a-dependent responses and receptor trafficking. Xenopus calcium-branch and rodent neuronal experiments retain their separate systems and do not by themselves establish a particular human FZD4 G-protein coupling mechanism.
Norrin is a non-Wnt ligand. The authentic abstract of PMID:15035989(https://pubmed.ncbi.nlm.nih.gov/15035989/) supports high-affinity Norrin–FZD4 recognition and the FZD4/LRP receptor system; complete original text was not recovered. PMID:17955262(https://pubmed.ncbi.nlm.nih.gov/17955262/) supports cell-surface binding and signaling within its abstract-level access. PMID:19837032(https://pubmed.ncbi.nlm.nih.gov/19837032/) supplies selected original mouse endothelial signaling and barrier evidence, including cerebellar vascular-barrier integrity. These observations do not resolve every older cerebellar morphogenesis or extracellular-matrix-input assertion. Short excerpts supporting the receptor roles, regulation and response interpretations have exact normal-cache byte locators in the evidence archive. The retinal role is included in the Norrin core because FZD4 supplies the endothelial signal-reception step, not merely because mutations cause a vascular phenotype.
kd:1.0x10(molar) field are not treated as measured 10-M affinity or proof of no interaction. IL16, FRMPD2, CIPP and LNX1 have positive original-domain rows beyond the zero-valued imported subset. For raw 26, incoming Q86UT5 remains distinct from the retained IntAct Q86UT5-2 participant; neither identifier is silently substituted. Peptide/domain binding does not establish full-length endogenous complexes.Wild-type surface localization is supported separately from mutant ER trapping and engineered structural constructs. The FZD4 comparator in original Figure 2 of PMID:19643732(https://pubmed.ncbi.nlm.nih.gov/19643732/) supports surface residence despite the paper's FZD5-focused internalization results. HPA provides supported antibody-localization metadata; individual images were not independently scored. ARBA supplies a computational cell-surface prediction, not a new experiment or a completed target-condition audit.
Mouse donor evidence supports specialized synaptic and junctional contexts. The indexed original Results/Figure 1 of PMID:16501258(https://pubmed.ncbi.nlm.nih.gov/16501258/) supports hippocampal Fzd4/PSD-95 colocalization, and the official Figure 4 caption of PMID:15195140(https://pubmed.ncbi.nlm.nih.gov/15195140/) supports epithelial-contact localization. The abstract of PMID:25424568(https://pubmed.ncbi.nlm.nih.gov/25424568/) supports neuronal morphogenesis but does not expose the precise dendrite-localization assay, leaving those transferred location contexts unresolved. These donor observations are not relabeled as human experiments.
The actual PTHR11309 tree and alignment place human FZD4 beneath all six relevant IBDs: five at PTN000139394 and the retina-development assertion at PTN002601720. The target alignment reproduces all 537 residues. Current incoming and retained main/global donor sets differ for raw 36, 65, 72 and 88 and match for raw 50 and 77; both source versions remain preserved. Donor count and legitimate target self-membership are not defects. Biological relevance is assessed separately from correct node inheritance.
All 28 Reactome records were read as the existing cellular-component contexts. Selected explicit WNT5A:FZD4 events support receptor surface and internalization context; general coated-pit and uncoating events describe receptor cargo rather than catalytic functions of FZD4. PKC, phosphoinositide enzymes, HSPA8 and dynamin retain their own activities. No complete transitive participant-graph audit or physical FZD4 G-protein-contact claim is implied.
The literal extension groups remain attached to their original rows: raw 39 has input UniProtKB:P41221; raw 47 occurs in CL:0002608 and is part of GO:0016055 in one group; raw 59 and 86 occur in CL:0002608; raw 124 retains its original part_of CL:0002608 relation. No relation is silently repaired or transferred to another annotation.
The 60 manually assessed references cover all 55 original reference IDs and five additional identity or donor sources. Unused UniProt bibliography is not automatically promoted to a curated reference. Normal-source planning covers 80 paths, including the four separately qualified publications 12429992, 15195140, 16501258 and 19837032. Genuine native acquisition is complete: all 134 original contexts reconcile bijectively to the native 16-column TSV and generated seed. The evidence archive retains actual native joins; the superseded forecast remains private provenance. All 80 normal sources are present, comprising 47 unchanged main files and 33 newly acquired files.
Retained main-cache availability and external original reading are recorded separately. An abstract-only or absent normal cache does not erase a successfully read original, and a saved XML file is not a claim that every section or figure was read. The per-reference assessments record the scientific access boundaries; the smaller YAML archive retains portable source URLs, checksums and quote locators. Its column tables reconstruct all original fields, including literal donor and extension structure; it contains no current reviews, copied reference assessments or duplicated core functions. The genuine raw/export/seed comparison preserves all original contexts and six extension atoms, including the conjunction at raw 47. The two official display fields added for native export are recorded separately from the unchanged original annotation objects. The two biological questions retain their context within schema-supported question text.
The positive PMID:36115835 supplementary workbook measurements directly name the PDZ domains tested against the FZD4 terminal peptide. Thirteen positive contexts are refined to PDZ domain binding; eight unresolved contexts remain unchanged. Selected row identifiers and numerical measurements are available in the compact source archive. The PMID:20802536 original separately establishes the NHERF1 PDZ2 interface, whereas its Figure 6 Dvl2 recruitment experiment does not map the Dvl2 interface. The two Norrin partner rows are refined to cytokine binding. Other positive associations retain their original experimental scope under the immutable project policy.
The transcription terms describe regulation, not transcription-factor molecular activity. Human FZD4-dependent Topflash/TOP-FOP output is positive evidence for that regulation. The original PMID:14688793 Figure 4h caption identifies the SuperTOPflash experiment even though the complete article is unavailable. The receptor's membrane location does not refute regulation through beta-catenin signaling.
GO:0071300 explicitly includes altered gene expression. The authentic PMID:12429992 review abstract reports FZD4 induction after ATRA in human NT2 cells. That positive observation is retained, but it does not resolve the FZD4 product role asserted by the original ISS annotation. Both ISS rows name WNT7B/P56706 rather than a Frizzled ortholog, and the intended transfer remains unadjudicated; both are now UNDECIDED. The two source-defect CHECK records and literal identifiers remain unchanged. WNT7B is also named in the review abstract, but that co-mention does not establish how the incorrect donor arose, so its cause remains UNKNOWN. The decision is specific to this unresolved evidence chain and does not impose a general rule against expression-response annotations.
The checked is_a ancestry for Norrin signaling does not include cytokine-mediated signaling. The broad cytokine context therefore remains non-core; no unverified formal edge is used to justify a TOO_GENERAL action. Selected mouse cerebellar results in PMID:19837032 establish vascular integrity and stability; they do not independently expose the older donor's generation-and-organization experiment, so the cerebellar morphogenesis annotation remains unresolved.
External numerical claims remain source-qualified. The PMID:19388021 original Table II is an indexed original table; its internal-peptide IC50 values are not affinity constants. The Haenig original article and supplements provide Table S2 NN1.0. No invented normal-cache quotation substitutes for those separately read original tables.